Holub Jan, Meckel Marian, Kubíček Vojtěch, Rösch Frank, Hermann Petr
Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030, 128 43, Prague 2, Czech Republic.
Contrast Media Mol Imaging. 2015 Mar-Apr;10(2):122-34. doi: 10.1002/cmmi.1606. Epub 2014 May 6.
Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.
制备了通过乙酰胺（NOTAM(BP)）或亚甲基次膦酸酯（NO2AP(BP)）间隔基连接到1,4,7 - 三氮杂环壬烷 - 1,4 - 二乙酸片段上的偕二（膦酸）配体，这些配体是为（68）Ga设计的。在化学（高反应物浓度）和无载体添加（68）Ga的放射性标记研究中，具有亚甲基次膦酸酯间隔基的配体的Ga(III)络合比具有乙酰胺间隔基的配体快得多。对于这两种配体，由于双（膦酸酯）基团的强笼外结合，Ga(III)络合物的形成比与NOTA的形成慢。仅在60℃以上且在狭窄的酸度区域（pH约为3）时，放射性标记才高效且快速。在较高温度下，在络合反应过程中观察到羧酰胺 - 双（膦酸酯）共轭物的酰胺键水解，导致形成Ga - NOTA络合物。体外吸附研究证实（68）Ga络合物与羟基磷灰石有效结合，与帕米膦酸等常见双（膦酸酯）药物的结合情况相当。通过离体生物分布研究和体内正电子发射断层扫描成像在健康大鼠中证实了选择性骨摄取。骨摄取非常高，注射后60分钟时[(68)Ga]NO2AP(BP)的标准化摄取值（SUV）为6.19±1.27，优于先前报道的基于（68）Ga - DOTA的双（膦酸酯）和[(18)F]NaF的摄取（注射后60分钟时[(68)Ga]DO3AP(BP)和[(18)F]NaF的SUV分别为4.63±0.38和4.87±0.32）。巧合的是，软组织中的积累通常较低（例如，注射后60分钟时[(68)Ga]NO2AP(BP)在肾脏中的SUV为0.26±0.09），这表明新的（68）Ga络合物是用于钙化组织的无创、快速和定量成像以及使用PET或PET/CT对转移病灶成像的理想示踪剂。
